The regulation of osteoclastic bone resorption is a precise, complex process. Involving a number of mediators and cell types. Osteoblast are among the major cells responsible for both recruitment and activation of osteoclasts. They act in a variety of ways to effect osteoclast development (synthesis of bone matrix components and exposure of mineralized surfaces as chemoattractants for osteoclast precursors) and osteoclast function (release of paracrine factors in response to known stimulators of resorption). Thus, the regulation of bone resorption is being unceasingly understood as linked to osteoblast and their products. This proposal uses 3 different osteopetrotic mutations in the rat, with known reductions in bone absorption and aberrations in bone matrix components and bone cell proliferation, to Explore the regulation of bone resorption by osteoblast and bone matrix constituents. These studies are expected to provide insights into the cellular and Molecular bases for the regulation of bone resorption and have application in situations where selective regional or general reductions or accelerations of bone absorption are desirable. Our specific aims are to confirm and further characterize bone matrix and mineral abnormalities in these 3 mutations, to evaluate osteoblast biology and matrix synthesis in organ and cell cultures from osteopetrotic bone with emphasis on analyses of cell proliferation and synthesis of specific bone matrix components using oscotopic and molecular probes, and determination of the ability of mutant osteoblast and matrix products to recruit and direct differentiation and function of normal osteoclasts. To do this we shall use gel electrophoresis and HPLC to identify collagenous and non-collagenous proteins of bone matrix, density fractionation and x-ray diffraction to study bone crystal composition, size, development and NA trix-binding capacity, bone organ (calvariae) and osteoblast cultures to examine activation and/or synthesis of histones, TGFB, alkaline phosphatase, osteocalcin, osteopontin, collagen types and oncogenes using molecular probes, and mutant Metatarsal cultures and isolated normal osteoclasts to evaluate the ability of mutant bone and osteoblast to promote the development and function, respectively, of normal osteoclasts.